Radioisotopes, particularly halogen radioisotopes, have been used extensively in nuclear medicine. The preferred utility of radioiodine in nuclear medicine is based on the availability of relatively reliable techniques of incorporating radiohalogen atoms into organic compounds.
Many of the presently available radiohalogenation techniques have the common feature that a radionuclide is introduced into an organic compound by an organometallic reactant, such as organoborane. Traditionally, many radiohalogenated materials have been made by substitution reactions, most of which are nucleophilic. However, some useful electrophilic procedures are known. A major disadvantage of such substitution reactions is that, because the reaction rates are dependent upon the concentration of reagents, the radiohalogenation reactions do not work well on small scales. Consequently, one encounters many difficulties in synthesizing desired radiohalogenated compounds such as the rate of formation, separation of radiolabeled product from the organic starting material and side reactions such as solvent attack on the organic starting material. Yields of only 2–10% are not uncommon in such conventional synthetic procedures. Still another drawback is that the availability of suitable organic starting materials for the radiolabeling reaction is often limited. In many cases the desired substitution reaction does not occur.
An extremely important consequence of the above mentioned reaction rate problem is that no-carrier-added reagents are difficult to prepare. No-carrier-added reagents are very important because the quantity of radiopharmaceutical compound can be kept below picogram levels. This minimizes body loads and aids in the differentiation of receptor-sites.
Kabalka, U.S. Pat. No. 4,450,149, discloses a method for radiohalogenating organoborane compounds. According to Kabalka, the organoborane is reacted with a wide variety of halide salts in the presence of a mild oxidizing agent to provide a radiohalogenated compound. Boron-halogen exchange has been used for preparing a wide variety of radiopharmaceuticals. Initially, methods were developed to halogenate trialkylboranes but it was found that boronic acids and esters were more convenient to handle and could be prepared containing a wide variety of functional groups. However, the use of boronic acids as organohalogen precursors to pharmaceuticals has a disadvantageous propensity to form boroxines that are unstable to both air and water.
One disadvantage of most of the prior art methods of radiolabeling is that they require introduction of a radioisotope early in the construction of the desired molecule due to the fact that the methodologies do not tolerate many pharmacologically active functional groups. This is deleterious because many of isotopes of use in medicine have very short half-lives and will decay before synthesis is complete.
In the light of the above discussed difficulties of preparing radiohalogenated compounds by substitution reactions and despite the advances in radiohalogenation disclosed in Kabalka, a need continues to exist for an improved technique of radiohalogenating organic compounds in high yields and for a method that permits the attachment of a binding site for a radiolabel on an intermediate at any step in the synthesis of a final molecule to be radiolabeled, followed by attachment of the radiolabel at the site following synthesis of the final molecule.
Organotrifluoroborates have proven to be versatile intermediates in organic synthesis because of their remarkable chemical stability. They are crystalline solids that are stable to both air and water, and they are readily prepared. Vedejs et al, J. Organic Chemistry, 60:3020–3027 (1995) discloses a method for the conversion of aryl and alkyl boronic acids into potassium aryl and alkyl trifluoroborates, respectively, by addition of KHF2. Darses et al, European J. Organic Chemistry, 8:1875–1883 (1999) discloses a method for the production of aryl, alkenyl, and alkynyl trifluoroborates.